Composition, formulations & methods for prevention and treatment of diseases and conditions associated with bronchoconstriction, allergy(ies) and inflammation

Abstract

A pharmaceutical composition effective for preventing and alleviating bronchoconstriction, allergy(ies) and/or inflammation comprises a surfactant and a nucleic acid comprising an oligonucleotide anti-sense to an adenosine A 1 , A 2a , A 2b or A 3 receptor gene, mRNA, flanking regions or regions bridging the intro/exon borders, analogues which bind thymidine but have low adenosine content or exhibit lower or no adenosine receptor agonist activity, combinations thereof, physiologically acceptable salts thereof or mixtures thereof. The composition is formulated for administration by a multiplicity of routes for the prevention or alleviation of diseases and conditions associated with breathing difficulties, impeded and obstructed airways, bronchoconstriction, allergy and/or inflammation. Among the applications of this technology are the prevention and treatment of diseases and conditions such as asthma, kidney damage or failure, ARDS, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, pain, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), and cancers such as leukemias, lymphomas, carcinomas, and the like.

1 - 107 . (Cancelled).  
     
     
         108 . A pharmaceutical composition comprising an antisense oligonucleotide effective to alleviate hyper-responsiveness to adenosine or increased levels of adenosine, or to alleviate bronchoconstriction, asthma, or lung allergy, wherein said antisense oligonucleotide is 4 to 60 nucleotides long and comprises 15% or less adenosine, wherein said antisense oligonucleotide is antisense to a target polynucleotide, wherein said pharmaceutical composition is of a respirable or inhalable particle size.  
     
     
         109 . The pharmaceutical composition of  claim 108 , wherein the antisense oligonucleotide comprises 10% or less adenosine.  
     
     
         110 . The pharmaceutical composition of  claim 109 , wherein the antisense oligonucleotide comprises 5% or less adenosine.  
     
     
         111 . The pharmaceutical composition of  claim 110 , wherein the antisense oligonucleotide is adenosine-free.  
     
     
         112 . The pharmaceutical composition of  claim 108 , wherein the antisense oligonucleotide is 9 to 51 nucleotides long.  
     
     
         113 . The pharmaceutical composition of  claim 112 , wherein the antisense oligonucleotide is 18 or 21 nucleotides long.  
     
     
         114 . The pharmaceutical composition of  claim 108 , wherein the antisense oligonucleotide is antisense to the initiation codon, the coding region or the 5′ or 3′ intron-exon junction of a gene encoding a protein associated with hyper-responsiveness to adenosine, hyper-responsiveness to increased levels of adenosine, hyper-responsiveness to increased levels of an adenosine receptor, bronchoconstriction, asthma, lung allergy, or lung inflammation, or is antisense to the corresponding mRNA thereof.  
     
     
         115 . The pharmaceutical composition of  claim 108 , wherein the particle size is about 0.5 μm to about 10 μm in size.  
     
     
         116 . The pharmaceutical composition of  claim 108 , wherein the particle size is 10 μm to 500 μm in size.  
     
     
         117 . The pharmaceutical composition of  claim 108 , further comprising a surfactant.  
     
     
         118 . The pharmaceutical composition of  claim 108 , wherein the hyper-responsiveness to adenosine, hyper-responsiveness to increased levels of adenosine, hyper-responsiveness to increased levels of an adenosine receptor, bronchoconstriction, asthma, lung allergy, or lung inflammation is associated with allergy, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, respiratory distress syndrome, or a side effect of adenosine administration.  
     
     
         119 . The pharmaceutical composition of  claim 108 , wherein the antisense oligonucleotide is administered in an amount of about 0.01 to about 150 mg/kg body weight.  
     
     
         120 . The pharmaceutical composition of  claim 108 , wherein the antisense oligonucleotide is antisense to the initiation codon, the coding region or the 5′ or 3′ intron-exon junctions of a gene encoding an adenosine A 1  receptor, adenosine A 2b  receptor or adenosine A 3  receptor.  
     
     
         121 . The pharmaceutical composition of  claim 108 , wherein said antisense oligonucleotide comprises a sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7 to SEQ ID NO: 996.  
     
     
         122 . The pharmaceutical composition of  claim 108 , wherein said antisense oligonucleotide comprises wherein at least one mononucleotide linked or modified by one or more of phosphorothioate, phosphorodithioate, methylphosphonate, phosphoramidate, boranophosphate, phosphotriester, formacetal, 2′-O-methyl, thioformacetal, 5′-thioether, carbonate, 5′-N-carbamate,sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene (methylimino) and methyleneoxy(methylimino), terminal 1,3-propanediol, terminal dodecanol, 2′-O-methoxyethyl, C-5-propynyl pyrimidine, C-5 methyl cytidine, C-5 ethynyl pyrimidine, 2′ propoxy, C-18 amine, N3′-P5 phosphoramidates, 3′-alkylamino, 2′-fluoro pyrimidine, 5-fluoro pyrimidine, 5-iodo pyrimidine, 5-bromo pyrimidine, 2′-borano, C-5 hexynyl pyrimidine, 2′-O-(2-methoxy)ethyl, 2′-O-aminopropyl, 5-(phenylethyl) or a peptide nucleic acid interbase linkages or conjugated to a polyethylene glycol, cholesterol, cholesteryl, dehydroepiandrosterone, dehydroepiandrosterone sulfate, dehydroepiandrosterone sulfatide, ubiquinone, dolichol, poly L-lysine, sulfatidic acid or a fatty acid.